Progression-free Survival Hazard Ratio Research Articles

First-line CDK4/6 inhibitor-based combinations for HR+/HER2- advanced breast cancer: A Bayesian network meta-analysis.

International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA). We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines. Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA=78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA=94.1%), abemaciclib+NSAI (SUCRA=69.9%), and ribociclib+NSAI (SUCRA=68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision. Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).

Antibiotic use reduces the efficacy of immune checkpoint inhibitors in patients with urothelial carcinoma: A systematic review and meta-analysis

ContextAntibiotics have been suggested to diminish the efficacy of immune checkpoint inhibitors (ICIs) by alterations of the gut microbiota. ObjectiveTo perform a meta-analysis summarizing the effect of antibiotics on the overall survival (OS) and progression-free survival (PFS) of urothelial cancer (UC) patients receiving ICI. Evidence acquisitionPubMed, EMBASE (Ovid), and the Cochrane Library were searched to identify studies published up to July 14, 2023. Studies reporting the associations between antibiotics use and OS and PFS in UC patients treated with ICI were included in this systematic review and meta-analysis. The random-effect model was used to pool the Hazard Ratios (HRs) for OS and PFS with 95% confidence interval (95%CI). The ROBINS-I was used to assess the risk of bias in the included studies, while the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to inform the quality of evidence. Evidence synthesisThirteen nonrandomized studies involving a total of 5,095 ICI-treated UC patients were included in this review, of which 1434 (28%) received antibiotics. Overall, compared to patients who did not receive antibiotics, the pooled HRs for OS and PFS in those who received antibiotics were 1.45 [95% CI 1.25–1.68] and 1.40 [95% CI 1.05–1.87], respectively. Subgroup analysis revealed that the types of ICI and timing of antibiotic initiation did not influence the effect of antibiotics on OS and PFS in UC patients (P > 0.05). ConclusionsAntibiotic use significantly reduced OS and PFS in UC patients receiving ICI. While antibiotics remain crucial for the treatment of infections in UC patients, antibiotics should be prescribed cautiously in UC patients receiving ICI. Patient summaryAntibiotic use is associated with worsened survival in UC patients receiving immune checkpoint inhibitors.

Differential Effect of Consolidative Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer Based on Sex

BackgroundThe landmark CREST trial demonstrated that consolidative thoracic radiotherapy (cTRT) improved overall (OS) and progression-free survival (PFS) after initial chemotherapy (chemo) in extensive-stage small cell lung cancer (ES-SCLC), with potentially increased benefit in women compared to men. It is unknown whether similar findings would apply after chemoimmunotherapy (chemo-IO) became the standard first-line treatment. In this analysis, we report national practice patterns and survival outcomes of cTRT according to patient sex. MethodsWe included patients from a nationwide de-identified electronic health record-derived database diagnosed with stage IV SCLC (2014-2021) who completed 4-6 cycles of first-line systemic therapy (platinum-doublet chemo or chemo-IO). We evaluated OS and PFS using multivariable Cox proportional hazards regression with receipt of cTRT as an independent variable and stratified by sex. As a sensitivity analysis, we weighted the models by the inverse probability of receiving cTRT. ResultsA total of 1,227 patients were included (850 chemo, 377 chemo-IO). There were no statistically significant differences in baseline characteristics between patients who did and did not receive cTRT. Among women, cTRT was associated with superior OS (adjusted hazard ratio (HR) 0.67; 95% confidence interval [CI] 0.52-0.87) and PFS (HR 0.63; 95% CI 0.49-0.82) compared to those not receiving cTRT. Conversely, no OS or PFS benefit with cTRT was observed in men [(OS HR 1.03; 95% CI 0.80-1.31; PFS HR 1.12; 95% CI 0.85-1.47)]. Findings were similar in weighted analyses. ConclusionThe survival efficacy of cTRT may be moderated by sex, with female patients appearing more likely to benefit than male patients. These findings reflect sex-based survival trends with similar effect sizes to those observed in the CREST trial. While the underpinnings of this association need to be elucidated, stratification by sex should be considered for RCTs studying cTRT in ES-SCLC.

Maintenance and consolidation strategies for patients with untreated advanced follicular lymphoma: A systematic review and network meta-analysis of randomized trials.

The emergence of novel and efficient antibody maintenance approaches has provided more options for post-induction treatment of advanced follicular lymphoma (FL), and further comparisons are required to determine the most clinically beneficial regimen. The authors conducted a systematic review and meta-analysis to evaluate the maintenance or consolidation strategy. The authors performed two independent searches in PubMed, Web of Science, the Cochrane library databases, Scopus, and Embase for randomized controlled trials (RCTs) evaluating maintenance or consolidation therapy in untreated FL patients. Extracted data included the clinical characteristics, treatment regimen, progression-free survival (PFS), overall survival (OS), and adverse effects. They then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. The authors screened 1515 records and identified 13 eligible RCTs that assessed nine different regimens in 5681 advanced FL patients. Reconstructed individual survival data presented that obinutuzumab had the highest effect sizes and certainty of the evidence for PFS (hazard ratio, 0.43; 95% confidence interval, 0.22-0.79) and tolerability compared with observation. However, no benefit was observed in patients according to the OS, regardless of which regimen was taken. Considering other regimens, although an extended course of rituximab maintenance and consolidation therapies presented PFS benefits compared with standard rituximab maintenance, they were also associated with higher toxicity. Although obinutuzumab and rituximab maintenance treatment improved PFS significantly, its clinical benefit requires further validation in larger populations. Furthermore, because few trials informed each treatment comparison, research is needed to refine the understanding of this complex and rapidly evolving treatment landscape.

Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer

Aim Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. Methods Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. Results Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. Limitations Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. Conclusions We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison.

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P<0.01), except for pneumonia, which was similar. These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

Telomere Length and DNA Methylation Epitype Both Provide Independent Prognostic Information in CLL Patients; Data from the UK CLL4, Arctic and Admire Clinical Trials

The presence of TP53 aberrations ( TP53ab) and/or unmutated IGHV genes (U-CLL) helps select initial treatment for CLL patients (Hallek 2018 &amp; Walewska 2022). However, many other biomarkers identified in recent years have failed to impact clinical decisions due to their coexistence with poor-risk indicators and uncertainty in their predictive abilities, often without suitable validation in long-term Phase II/III trials with comprehensive molecular analysis. We evaluated the clinical significance of two biomarkers, DNA methylation-based epitype (DME) and telomere length (TL), in (immuno-)chemotherapy clinical trials using samples from UKCLL4 (n=304) and ARCTIC/ADMIRE (ARC/ADM) (n=215). To our knowledge, DME and TL have not been assessed in a single study. Therefore, we utilized previously published DME (Wojdacz, 2019) and TL data (Strefford, 2015 &amp; Norris, 2019), supplemented with new MMQ-PCR data (n=60). TL cut-offs of short (TL-S, &amp;lt;2.92kb), intermediate (TL-I, 2.92-3.57kb), and long (TL-L, &amp;gt;3.57kb) and DME classifications of n-CLL (naive B-cell-like), i-CLL (intermediate B-cell-like) and m-CLL (memory B-cell-like) were employed. 73% of m-CLL and 50% of n-CLL patients harboured TL-L and TL-S, respectively (p&amp;lt;0.001, Figure 1). Additionally, n-CLL and TL-S were associated with poor-risk indicators, such as TP53ab and del(11q) (p&amp;lt;0.05, Figure 1). We then assessed the impact of 10 clinico-biological features, including DME, TL, age and treatment arm, on progression-free survival (PFS) and overall survival (OS) in CLL4 and ARC/ADM cohorts using univariate analysis (UA). The n-CLL group exhibited the shortest PFS and OS in the ARC/ADM cohort (PFS hazard ratio (HR):4.47, 95% confidence interval (CI):2.56-7.82 &amp; OS HR:3.95, CI:1.66-9.35, p&amp;lt;0.01), greater than the presence of TP53ab (PFS HR:4.39, CI:2.69-7.17 &amp; OS HR:3.77, CI:1.94-7.33, p&amp;lt;0.001). In CLL4, whilst TP53ab was the strongest predictor of PFS and OS (PFS HR:3.61, CI:2.39-5.44 &amp; OS HR: 3.66, CI:2.4-5.57, p&amp;lt;0.001), both n-CLL (PFS HR:1.96, CI:1.32-2.9 &amp; OS HR:2.8, CI:1.81-4.34, p&amp;lt;0.001) and TL-S (PFS HR:2.36, CI:1.7-3.29 &amp; OS HR:2.66, CI:1.87-3.76, p&amp;lt;0.001) were in the top five predictors of PFS and OS along with U-CLL and biallelic ATM inactivation ( biATM). Next, we performed Kaplan-Meier subgroup analysis, investigating DME in TL subgroups and vice versa. Examination of both biomarkers in the opposing subgroups in the ARC/ADM cohort, showed that TL could further stratify the i-CLL subgroup, with TL-L predicting longer PFS (median:6.12 years) compared to TL-S (HR:5.78, CI:2.34-14.33, median:3.8 years, p&amp;lt;0.001) or TL-I (HR:3.29, CI:1.4-7.76, median:4.35 years, p&amp;lt;0.01). As this pairwise analysis suggested that DME and TL may differentially contribute to outcome, we performed a multivariate cox regression, whilst controlling for confounding variables such as TP53ab and U-CLL. Covariates that were significant in UA were included in a stepwise backwards elimination process until a final model was reached. The CLL4 models were based on 246 subjects with 221 PFS and 205 OS events, ARC/ADM models were based on 138 and 176 subjects with 86 and 45 events for PFS and OS, respectively. For PFS models, TL-S emerged as significant (CLL4 HR:2.14, CI:1.39-3.3, p&amp;lt;0.001 &amp; ARC/ADM HR:2.18, CI:1.17-4.05, p&amp;lt;0.01) with a HR lower than TP53ab (CLL4 HR:3.38, CI:2.13-5.37 &amp; ARC/ADM HR:4.94, CI:2.58-9.48, p&amp;lt;0.001). DME emerged as significant for PFS in the CLL4 cohort (n-CLL HR:2.35, CI:1.37-4.05, p&amp;lt;0.01), along with SF3B1 mutation and treatment arm (Figure 2). In ARC/ADM, U-CLL, TP53ab, TL-S, del11q and biATM emerged as significant predictors of PFS (Figure 2). For OS, in both cohorts, TP53ab (CLL4 HR:2.77, CI:1.74-4.4, p&amp;lt;0.001 &amp; ARC/ADM HR:3.28, CI:1.64-6.55, p&amp;lt;0.001) and DME (CLL4 HR:2.07, CI:1.15-3.73, p&amp;lt;0.05 &amp; ARC/ADM, HR:3.4, CI:1.14-10.12, p&amp;lt;0.05) were found to predict shorter survival (Figure 2). Currently, we are integrating additional IGHV/IGLV data into our analysis, including the presence of IGLV3-21R110. In conclusion, by assessing the individual contribution of DME and TL to disease survival, we found that both variables offer valuable independent prognostic information when included in statistical models with poor-risk genomic lesions. TL and DME could help identify IGHV-mutated patients destined to respond poorly to (immuno-)chemotherapy, that might be more favourably treated with targeted agents.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

Autologous Stem Cell Transplant in Fit Patients with Late Relapsed Diffuse Large B-Cell Lymphoma That Responded to Salvage Chemotherapy

Background: The new standard of care for fit patients with refractory or early relapse of diffuse large B-cell lymphoma (DLBCL) is chimeric antigen receptor T-cell (CAR-T) therapy. However, for patients with a relapse ≥12 months after completing frontline therapy, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care. There is a need to characterize such patients and their survival in view of the recent shift in treatment paradigm. Methods: Patients with DLBCL that relapsed ≥12 months after R-CHOP or R-CHOP-like frontline therapy who underwent salvage therapy and ASCT at Mayo Clinic or University of Iowa between 07/2000 and 4/2020 were identified from institutional lymphoma and transplant databases. Clinical characteristics, treatment information, and outcome data were abstracted. Progression-free survival (PFS) and overall survival (OS) from the time of ASCT were analyzed using Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were performed in JMP v15. Results: A total of 158 patients with late relapsed DLBCL who underwent salvage chemotherapy and ASCT were identified. Baseline characteristics at relapse/ASCT are shown in Table 1. Median time from frontline therapy completion to 1st relapse was 26.4 months (range 12.0-152.4). Median age at relapse was 63 years (range 19-77), and 96 (61%) patients were male. A minority (3; 3%) had ECOG PS ≥2. 43 (52%) patients had an elevated serum LDH level, 70 (65%) had advanced stage disease, and 12 (11%) had &amp;gt;1 extranodal involvement. Median line of salvage therapy was 1 (range 1-3), and 17 (11%) patients required &amp;gt;1 line of salvage therapy. Best response before ASCT was complete response (CR) in 97 (61%) and partial response (PR) in 61 (39%). Median age at ASCT was 64 years (range 19-78). Median follow-up after ASCT was 91.5 months (95% CI 74.0-103.3). Median PFS and OS were 54.5 (95% CI 31.9-77.8) and 99.8 (95% CI 60.3-144.5) months, respectively. The 2-year PFS and OS rates were 64% (95% CI 56-71) and 81% (95% CI 74-87), respectively. No statistically significant difference in PFS was seen based on age at ASCT, sex, serum LDH, stage, or extranodal site involvement of &amp;gt;1 at relapse (Table 2). However, patients who required &amp;gt; 1 line of salvage therapy, compared to those requiring 1 line of salvage therapy, had significantly inferior PFS (median 6.1 vs 61.8 months, P &amp;lt;0.0001) and OS (17.8 vs 111.7 months, P &amp;lt;0.0004). There was no statistically significant difference in survival in patients who achieved CR vs PR prior to ASCT, with a median PFS of 61.8 vs 37.8 months( P=0.21) and a median OS of 111.7 vs 78.3 months ( P=0.62). Patients who achieved CR after 1 line of salvage therapy had the most favorable PFS and OS, with a median PFS of 65.6 vs 45.4 vs 6.1 vs 7.6 months ( P=0.0004) and a median OS of 133.0 vs 88.9 vs 24.2 vs 17.6 months ( P=0.004) in patients achieving CR after 1 line of salvage therapy vs PR after 1 line of salvage therapy vs CR after &amp;gt;1 line of salvage therapy vs PR after &amp;gt;1 line of salvage therapy, respectively (Table 2). In multivariate Cox regression models adjusted for age at ASCT and sex, patients requiring &amp;gt; 1 line of salvage therapy, compared to those who required 1 line of salvage therapy, had significantly inferior PFS with a hazard ratio (HR) of 3.25 (95% CI 1.82-5.78, P &amp;lt;0.0001) and OS with a HR of 3.50 (95% CI 1.86-6.60, P=0.0001). However, there remained no significant difference in survival based on response status (CR vs PR) with a HR for PFS 0.78 (95% CI 0.52-1.17, P=0.23) and OS 0.93 (95% CI 0.58-1.47, P=0.74). Conclusions: Survival after ASCT was excellent in patients with late relapsed DLBCL achieving CR after 1 line of salvage chemotherapy. Favorable survival outcomes were seen in patients who achieved PR after 1 line of salvage therapy. These data support the current clinical practice of ASCT consolidation in these patients. However, post-ASCT survival was poor in patients who required more than 1 line of salvage chemotherapy, despite achieving a satisfactory response to subsequent lines of salvage therapy. Alternative treatment strategies such as CAR-T therapy should be considered in such patients.

CD5 Expression in Mature T Cell Lymphoma

Background Mature T-cell lymphoma (TCL), an aggressive and heterogenous group of T cell neoplasms, constitutes less than 15% of adult non-Hodgkin lymphomas. CD5 is an inhibitory T cell receptor molecule expressed on mature T cells. CD5 expression has been associated with worse outcomes in B-cell malignancies, however this association has not been explored in TCL. Furthermore, CD5 has become a promising immunotherapeutic target for TCL. We herein aimed to characterize CD5 expression in TCL subtypes at diagnosis and relapse, and its association with clinical features and outcomes in a single center cohort. Methods We retrospectively identified 109 patients (pts) diagnosed with non-cutaneous and non-leukemic mature TCL, with data on CD5 expression on tumor tissue by immunohistochemistry (IHC) and/or flow cytometry (FC), from the electronic medical records at the Hospital of the University of Pennsylvania (HUP). CD5 positivity (CD5+) was defined as any percentage of CD5+ malignant cells on FC and/or IHC. Chi-square test was used to compare baseline pt characteristics at the initial presentation between CD5 expression groups. Treatment response (TR) was defined as achieving complete or partial response by the end of initial treatment. Logistic regression models were used to assess the impact of clinical parameters on the overall TR rate and odds ratios (OR) were computed. Cox proportional hazards models were used to evaluate the effects of clinical parameters on overall survival (OS) and progression-free survival (PFS) and were reported as hazard ratios (HR). We also conducted Kaplan-Meier (KM) analyses for OS and PFS by CD5 expression status. The OR and HR are reported with 95% CI in brackets. P-values &amp;lt;0.05 were considered significant. All analyses were conducted in SAS version 9.4 (SAS Institute Inc). Results We collected and evaluated data from a total of 109 adult pts diagnosed with TCL at HUP between 1/1/05-1/1/21. Median age at diagnosis was 58 (range: 19 - 86 years); 56% were men; the most common diagnosis was ALCL (n=37) followed by nodal TFH lymphoma (n=29), PTCL-NOS (n=16), ENKTCL (n=13) and other extranodal (EN) TCL (n=14) (Table.1). Compared to CD5- pts, a higher percentage of CD5+ pts were diagnosed at age &amp;gt;60 (CD5-:34.7%, CD5+:55.0%, p=0.0343), and stage 3 or 4 (CD5-:46.9%, CD5+:70%, p=0.0142), but fewer CD5+ pts had EN involvement at diagnosis (CD5-:77.6%, CD5+:50%, p=0.0031). CD5 was also differentially expressed by TCL subtypes: nearly all TFH TCL (93.1%) and PTCL-NOS expressed CD5 (87.5%), whereas CD5 was less commonly expressed in ALCL (39.4%,), other ENTCL (27.8%), and ENKTCL (7.7%) (p&amp;lt;0.0001). In addition, on univariate analysis (UVA), CD5 expression was associated with stage 3 or 4 (p=0.014), age &amp;gt;60 (p=0.034), and less common EN involvement (p=0.031), but not with treatment response, relapse or survival. On UVA for treatment response, established risk factors such as ≥ 2 EN involvement (OR=0.25 [0.09, 0.6], p=0.0243) and high LDH (OR=0.26 [0.08, 0.85], p=0.0267), were shown to be negative predictors. Multivariate analysis (MVA) for response also predicted high LDH as a negative predictor (OR=0.29 [0.08,0.99], p=0.0477). CD5 expression was not associated with treatment response on either UVA (OR=1.18 [0.50, 2.78], p=0.7042) or MVA (OR=1.00 [0.33,3.60], p=0.9969). On UVA, CD5 positivity did not impact OS (HR=1.2 [0.7,2.0], p=0.6118) nor PFS (HR=1.5 [0.7,3.0], p=0.2862), while worse outcomes were associated with established risk factors, including ECOG performance status ≥ 2 (OS HR=2.0 [1.0-3.8], p=0.0440), ≥2 EN involvement (OS HR=3.1 [1.7-5.7], p=0.0002; PFS HR 13.1 [2.9-59.9], p=0.0009), and B symptoms (OS HR=2.1 [1.2-3.7], p=0.0117). TFH TCL was also found to be associated with worse OS (HR= 2.6 [1.3-5.5], p=0.0101). In our cohort of 35 pts with CD5 expression data at relapses, 100% pts remained CD5+ (n=19), 68.75% pts remained CD5- (n=11), but 31.25% pts gained CD5 expression (n=5), and none lost CD5 expression. Based on KM analyses, CD5 expression did not impact PFS or OS (Fig. 1). Conclusions In this cohort of 109 TCL pts, CD5 expression was common in TFH TCL, PTCL-NOS, ALCL, and ENTCL, and was retained or gained at relapse, thus supporting its potential as a therapeutic target. CD5 expression was associated with advanced age and stage, while EN involvement was less common. CD5 expression was not associated with a differential treatment response, PFS, nor OS.

Chimeric Antigen Receptor (CAR) T Cell Infusion for Large B Cell Lymphoma in Complete Remission: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Introduction Axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) have been approved for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). In some cases, patients are identified as being in radiographic complete remission (CR) after CAR T cell manufacturing. However, there are limited studies with small sample sizes that have reported outcomes for this specific group, and prospective data are lacking. We hypothesize that patients with LBCL who are in CR prior to CAR T cell infusion have favorable progression-free survival (PFS) and overall survival (OS) with lower toxicity. Methods We analyzed CIBMTR registry data from adult patients with LBCL who received commercial axi-cel, liso-cel, or tisa-cel infusion between 2018 and 2021 while in radiographic CR. Kaplan-Meier estimators were used to assess PFS and OS. The cumulative incidence of relapse, non-relapse mortality (NRM), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) was reported according to the consensus ASTCT criteria. Univariable hazard ratios (HR) for PFS and OS were analyzed using a Cox regression model to evaluate the prognostic impact of each variable. A forest plot was generated to display relevant factors. Results A total of 134 LBCL patients in CR prior to CAR T cell infusion were identified across 53 centers. The median follow-up was 24.3 months (range 0.9-49.4). Baseline demographics are presented in Table 1. After CAR T infusion, 7/134 patients (5.2%) proceeded to subsequent transplant (6 allogeneic, 1 autologous). At two years post-infusion, the probability of PFS and OS was 43.5% (95% CI 34.4-52.8) and 63.8% (95% CI 54.4-72.6), respectively. The cumulative incidence of NRM at two years was 9% (95% CI 4.5-15.4), and the incidence of relapse/progression was 47.3% (95% CI 38.2-56.6). The rate of grade 3 or higher CRS was 3/134 (2.2%), with median time to onset of 3 days (range 1-16). Grade 3 or higher ICANS occurred in 11/134 (8.2%) with a median time to onset of 6 days (range 2-15). On univariate analyses, PFS was worse in patients with 5 or more lines of prior therapy before CAR T cell infusion (HR 2.39, 95% CI 1.18-484) (see Figure 1). The most common cause of death was relapse or disease progression, accounting for 26/46 (56.5%) deaths, followed by infection (8/46, 17.4%, including 4 (8.7%) from COVID-19), ICANS (2 out of 46, 4.3%), and other causes. Conclusions CAR T cell infusion in patients with LBCL who are in CR after receiving two or more lines of prior therapy is feasible, with a subset of patients remaining free of progression at two years. The high NRM rate of 9% at two years highlights the importance of continued follow-up in this at-risk population. The CIBMTR is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research.

Progression-Free Survival Efficacy in Refractory/Relapsed Multiple Myeloma among Elderly Patients: A Systematic Review.

Over the last decade, many studies have assessed the efficacy of treatments for refractory/relapsed multiple myeloma (R/R MM). While combination therapies show greater efficacy than traditional methods, limited research has targeted elderly patients who might be less resilient to treatments. Our study aimed to evaluate treatment efficacy for these elderly patients. We carried out a comprehensive review of the literature using a systematic approach. Initially, 4966 citations were retrieved and subsequently narrowed down to 13 eligible randomized controlled trials (RCTs) through our systematic review process from databases like Embase, PubMed, and Cochrane Library from 1 January 2000 to 31 December 2022. Evidence was collated through a frequentist network meta-analysis, using the hazard ratio (HR) for evaluation. Combined therapy of daratumumab, lenalidomide, and dexamethasone (DaraLenDex) was the preferred treatment for R/R MM elderly patients. Its strengths included an HR for progression-free survival (0.15; 95% CI: 0.09-0.25) and a 96% P-score. Our analysis suggests that, pending more comprehensive RCTs, DaraLenDex is the treatment with the highest efficacy for R/R MM in elderly patients.

Liposomal irinotecan plus fluorouracil/leucovorin in older patients with advanced pancreatic cancer: a single-center retrospective study.

The global phase 3 NAPOLI -1 trial of patients with pancreatic ductal adenocarcinoma (PDAC) demonstrated an overall survival (OS) benefit from using liposomal irinotecan and 5-fluorouracil/leucovorin (nal-IRI + 5-FU/LV) after treatment with gemcitabine (GEM) compared to 5-FU/LV alone. However, the efficacy and safety of this regimen in older patients are not well studied. We conducted a single-center retrospective study to compare the therapeutic efficacy of nal-IRI + 5-FU/LV between older and younger patients with cutoff ages of 70 and 75years, respectively. We included patients with a prior history of one or more GEM-based regimens for locally advanced or metastatic PDAC and were treated with nal-IRI + 5-FU/LV. Of the 115 patients, 54 (47.0%) and 24 (20.9%) were aged ≥ 70 and ≥ 75years, respectively. The median OS and progression-free survival (PFS) of the entire cohort were 8.5 and 3.6months, respectively. No significant differences were observed in OS and PFS hazard ratios using age cutoffs of 70 (P = 0.90 and 0.99, respectively) and 75 (P = 0.90 and 0.76, respectively) years. Additionally, no significant differences were found in the incidence of treatment-related adverse events (trAEs) between patients aged ≥ 70 and < 70years or those aged ≥ 75 and < 75years. Other than hematological toxicity, no trAEs higher than Grade 4 were observed in either age group. The efficacy and safety of nal-IRI + 5-FU/LV for patients with PDAC are not significantly different for those aged ≥ 70years compared to younger patients.

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study

Background: Ibrutinib (Ibr) is a once-daily Bruton tyrosine kinase (BTK) inhibitor approved in multiple regions for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (Ven) is a BCL-2 inhibitor approved in the US for pts with chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. Ibr and Ven have distinct and complementary modes of action, and the combination has shown promising clinical activity in early phase studies in MCL (Tam, N Engl J Med 2018; Wang, J Hematol Oncol 2021). Here, we report the primary analysis results from the multinational, randomized, double-blind, phase 3 SYMPATICO (NCT03112174) study comparing Ibr+Ven vs Ibr + placebo (Pbo) in pts with relapsed/refractory (R/R) MCL. Methods: Pts aged ≥18 y with R/R MCL after 1-5 prior therapies were randomly assigned 1:1 to receive oral Ibr 560 mg once daily concurrently with oral Ven (standard 5-wk ramp-up to a target dose of 400 mg once daily) or Pbo for 2 y, followed by single-agent Ibr until progressive disease (PD) or unacceptable toxicity. Randomization was stratified based on ECOG PS, prior lines of therapy, and tumor lysis syndrome (TLS) risk based on tumor burden and CrCl. The primary endpoint was progression-free survival (PFS) by investigator (INV) assessment using Lugano criteria; pts without PD or death were censored at the last non-PD assessment (per global censoring rules). Additional sensitivity analyses included PFS assessment by independent review committee (IRC) and censoring per US FDA rules (Table). Key secondary endpoints were tested hierarchically in the following order: complete response (CR) rate by INV assessment, time to next treatment (TTNT), overall survival (OS, interim analysis), and overall response rate (ORR) by INV assessment. Results: A total of 267 pts were enrolled and randomly assigned to receive Ibr+Ven (n=134) or Ibr+Pbo (n=133). Median age was 68 y; 96% of pts had an ECOG PS of 0-1, 17% had ≥3 prior lines of therapy, and 22% were at increased risk for TLS. At baseline, pts in the Ibr+Ven vs Ibr+Pbo arms had median ages 69 vs 67 y, high-risk simplified MCL International Prognostic Index score 38% vs 31%, bulky disease ≥5 cm 46% vs 40%, bone marrow involvement 46% vs 41%, splenomegaly 31% vs 25%, and TP53 mutated 30% vs 28%; other baseline characteristics were generally similar between arms. With a median time on study of 51.2 mo, median PFS by INV assessment was significantly longer with Ibr+Ven vs Ibr+Pbo (31.9 vs 22.1 mo), with a hazard ratio (HR) of 0.65 (95% CI, 0.47-0.88; stratified log-rank P=0.0052) (Figure). PFS rates at 24 mo were 57% and 45% with Ibr+Ven and Ibr+Pbo, respectively. PFS benefit with Ibr+Ven vs Ibr+Pbo was generally consistent across prespecified subgroups, including those with blastoid variant or TP53-mutated MCL. Sensitivity analyses of PFS were consistent with the primary analysis (Table). Ibr+Ven significantly improved CR rates (54% vs 32%) and TTNT (median not reached [NR] vs 35.4 mo); at the current 51.2 mo median follow-up, median OS was 44.9 mo with Ibr+Ven vs 38.6 mo with Ibr+Pbo (HR 0.85 [95% CI, 0.62-1.19]) (Table). Median duration of treatment was 22.2 mo for the Ibr+Ven arm and 17.7 mo for the Ibr+Pbo arm; at the time of analysis, 30% of pts in the Ibr+Ven arm and 20% of pts in the Ibr+Pbo arm remained on single-agent Ibr. Grade ≥3 adverse events (AEs) occurred in 84% of pts with Ibr+Ven vs 76% with Ibr+Pbo; the most frequent (occurring in ≥5% of pts) were neutropenia (31% vs 11%), pneumonia (13% vs 11%), thrombocytopenia (13% vs 8%), anemia (10% vs 3%), diarrhea (8% vs 2%), leukopenia (7% vs 0%), MCL (7% vs 12%), atrial fibrillation (5% vs 5%), COVID-19 (5% vs 1%), and hypertension (4% vs 9%). Serious AEs occurred in 60% of pts in each arm. No clinical TLS occurred; laboratory TLS occurred in 5% and 2% of pts in the Ibr+Ven and Ibr+Pbo arms, respectively. COVID-19 deaths occurred in 10 pts in each arm and had no meaningful impact on PFS or OS HRs. Conclusion: The Ibr+Ven combination demonstrated a statistically significant improvement in PFS compared with Ibr+Pbo in pts with R/R MCL; CR rates and TTNT were also significantly improved with Ibr+Ven. OS was numerically but not significantly improved at this interim analysis. The safety profile of Ibr+Ven was consistent with known AEs for each agent, with no new safety signals observed. Overall, these results demonstrate a favorable benefit-risk profile for Ibr+Ven in pts with R/R MCL.

Network Meta-Analysis of Randomized Trials in Relapsed/Refractory Multiple Myeloma: Relative Efficacy for Patients Who Are Lenalidomide-Refractory

Background: Continuous lenalidomide in combination with dexamethasone (Rd), with bortezomib and dexamethasone (VRd) or, more recently, with daratumumab and dexamethasone (DRd) is the standard first-line (1L) therapy for transplant-ineligible multiple myeloma (MM) patients (pts). Lenalidomide maintenance is the standard therapy after ASCT. As a result, more pts with MM become LEN-refractory at relapse, representing a difficult-to-treat population with a high unmet need for effective treatments. Selinexor is a first-in-class, oral, XPO1 inhibitor indicated for use in combination with bortezomib and dexamethasone (SVd) in adults with relapsed and refractory (RR) MM who have received at least one prior line. Efficacy and safety of SVd were evaluated in the BOSTON phase 3 randomized controlled trial (RCT) comparing SVd to bortezomib + dexamethasone (Vd). Extended follow-up of the BOSTON trial showed a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) with SVd vs Vd for the LEN-refractory subgroup (Mateos et al, EHA 2023). In the absence of head-to-head trials comparing SVd with other approved regimens in LEN-refractory subgroups, a network meta-analysis (NMA) was performed to evaluate the relative efficacy (PFS and OS) of SVd vs other treatment options in LEN-refractory pts. Methods: A systematic literature review (SLR) was conducted to identify the clinical efficacy and safety evidence of the approved treatments in Europe for RR MM. Searches were performed in Medline, Embase, Cochrane, and CRD up to February 2023. Following a feasibility assessment, the RCTs reporting PFS and/or OS hazard ratios (HRs) in the LEN-refractory subgroup were summarized in separate PFS and OS networks. Because these networks were disconnected, a two-step approach was implemented, beginning with a matching-adjusted indirect comparison (MAIC) followed by a random-effects Bayesian NMA. Based on clinical input, different prognostic factors and treatment effect modifiers were considered for the matching process in the MAIC: median age, sex, ECOG performance status, Revised-International Staging System, high-risk cytogenetics, prior ASCT, number of prior regimens, and median time since diagnosis. Results: Twelve RCTs (APOLLO, ASPIRE, BOSTON, CANDOR, CASTOR, ENDEAVOR, ELOQUENT-3, ICARIA-MM, IKEMA, MM-002, MM-003, and OPTIMISMM) were identified in the SLR reporting PFS and/or OS results for LEN-refractory pts. Three and two disconnected networks were formed for PFS and OS, respectively, which were linked through a MAIC by matching Vd pts in the BOSTON trial with the pomalidomide + dexamethasone (Pd) population of the MM-002 trial. Anti-CD38-based regimens approved in 2L+ RR MM, ie, daratumumab + Vd (DVd), daratumumab + carfilzomib + dexamethasone (DKd), and isatuximab + Kd (IKd) report the lowest PFS HRs vs Vd for LEN-refractory pts. SVd had the lowest PFS HR vs Vd (0.52, 95% CI 0.23-1.21) compared with the remaining comparators in the network. This includes SVd's direct comparators in the post-DRd population as per current ESMO MM guidelines: PFS HR of Kd vs Vd is 0.80 (95% CI 0.39-1.73) and PFS HR of pomalidomide + bortezomib + dexamethasone (PVd) vs Vd is 0.66 (95% CI 0.32-1.34), Figure 1. In the OS network, among the regimens included (with DKd, DVd and IKd excluded due to the lack of OS data on LEN-refractory pts), SVd also had the lowest OS HR vs Vd (0.53, 95% CI 0.22-1.28) compared with the other regimens, including Kd (HR vs Vd: 0.86, 95% CI 0.41-1.77), Figure 2. Conclusion: This is the first two-step approach NMA linking the disconnected networks of treatments available for LEN-refractory pts using efficacy results for this subgroup from their respective RCTs. Excluding anti-CD38-based regimens, which are unlikely to be used in a 2L+ setting with DRd increasingly prescribed in 1L, SVd is the most efficacious treatment option for LEN-refractory pts among commonly used combinations such as PVd, Kd, and pomalidomide-based regimens, with a reduction of 48% in the risk of progression vs Vd. Moreover, among the regimens included in the OS network, SVd had the largest OS improvement vs Vd. We hypothesize the substantial reduction for LEN-refractory pts in the risk of progression and death of SVd vs Vd compared to most of the regimens included in the NMA is due to the two different mechanisms of action with SVd.

Correlation between PFS and OS in FL: Implications for Clinical Trial Endpoint Selection

Introduction: Follicular lymphoma (FL) comprises 15% of all lymphoma cases and 70% of indolent lymphomas. Cytotoxic, targeted, and novel treatments lead to prolonged remission periods, with a median overall survival (OS) of greater than 10 years. For this reason, surrogate endpoints for OS are frequently used in clinical trials of FL to allow for quicker results and shorter time to drug approvals, as well as to offset the likely cost and difficulty in funding long term trials with OS as a primary endpoint. A frequently used surrogate endpoint is progression free survival (PFS); however, PFS has not been previously validated as a surrogate endpoint for OS in the treatment of FL. Previous systematic reviews of multiple trials did not have mature enough data to draw definitive conclusions (Zhu et al, AAPS J 2017). Methods: To evaluate the correlation between PFS and OS in FL trials, we conducted a comprehensive systematic review. We included all completed phase 2 or 3 clinical trials with posted results on ClinicalTrials.gov from the inception of the database until July 2023. Additionally, we manually added trials that were completed before the database inception in February 2000 culled from HemOnc.org. For inclusion, randomized controlled trials reporting a hazard ratio for both PFS and OS were considered. We performed statistical analyses, utilizing unadjusted linear regression weighted by sample size to evaluate the association between hazard ratios for PFS and OS. Results: A total of 169 randomized controlled trials for FL were initially identified. Upon screening, 74 randomized trials reported rates for both PFS and OS. 20 trials with 22 interventional arms that included hazard ratios were eligible for inclusion in final analysis. 21 (96%) phase 3 trials and 1 (4%) randomized phase 2 trial were included, encompassing 10,729 participants. Among the included interventional arms, 12 (55%) were in the first-line setting and 10 (45%) were in the refractory or relapsed setting. 14 (64%) arms demonstrated a PFS benefit, and 4 (18%) demonstrated both a PFS and OS benefit. Disease characteristics and treatment outcomes are included in Table 1. The correlation coefficient between PFS and OS was 0.558 (95% CI 0.545-0.571), indicating a weak association. The coefficient of determination was 0.311 (95% CI: 0.08-0.52) suggesting 31.1% of OS variance could be explained by changes in PFS (Figure 1). Discussion: PFS showed a weak correlation with OS in FL trials, challenging its role as a surrogate endpoint. Factors such as patient heterogeneity, treatment regimens, subsequent therapies, and treatment-related complications may contribute to the discrepancy. While PFS aids regulatory approval and drug development, our study suggests that PFS may not be an appropriate surrogate endpoint for OS in the treatment of FL, and alternative surrogate endpoints should be pursued. Possible alternative endpoints though will need to be validated using similar systematic methods given often contradictory findings between individual studies. For example, progression within 24 months of initial treatment (POD 24) was a valid surrogate endpoint for OS in the PRIMA study, however this was not the case in the GALLIUM study (Bachi et al., Blood Adv 2021). Other surrogate endpoints such as complete response rate at 30 months (CR30) have demonstrated strong correlation with PFS however their association with OS has yet to be established (Shi el, JCO 2016).

Efficacy of Isatuximab Combination Regimens in Patients with Relapsed and Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Management of relapsed refractory multiple myeloma (RRMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of anti-CD 38 monoclonal antibody is one of the major advances in the management of patients with multiple myeloma both in newly diagnosed and relapsed refractory settings. Isatuximab is an anti-CD38 antibody recently approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for RRMM. The purpose of our study is to explore and consolidate the efficacy of isatuximab combination regimens in patients with RRMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing isatuximab in patients with relapsed or refractory multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratios (RR) for overall progression free survival (PFS) and PFS in different subgroups based on cytogenetics, del (17 p) or t (4,14) statuses, overall survival (OS), overall response rate (ORR), including MRD negativity and complete response (CR). Heterogeneity was assessed with Cochran's Q -statistic. Fixed and random effects models were applied in assessing PFS, OS, and ORR, CR and MRD negativity. Results: Two phase III RCTs (ICARIA-MM and IKEMA) including a total of 609 patients with RRMM were eligible. ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. The randomization ratios were 1:1 in ICARIA-MM, and 3:2 in IKEMA studies. Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. The pooled HR for overall PFS was statistically significant at 0.59 (95% CI: 0.47-0.73; P &amp;lt; 0.00001). The PFS benefit was observed in different subgroups of cytogenetics, del (17 p) and t(4,14) statues; non-high-risk cytogenetic cohort (HR, 0.55; 95% CI: 0.40- 0.75; P = 0.0001), non del (17 p) cohort (HR, 0.55; 95% CI: 0.41- 0.72; P &amp;lt; 0.0001), t(4,14) cohort (HR, 0.52; 95% CI: 0.28- 1.0; P = 0.05), and non t(4,14) cohort (HR, 0.54; 95% CI: 0.41- 0.72; P &amp;lt; 0.0001). The pooled HR for PFS was not statistically significant in high-risk cytogenetic cohort at 0.68 (95% CI: 0.42- 1.11; P = 0.13) and del (17 p) cohort at 0.79 (95% CI: 0.39- 1.60; P = 0.52). The pooled HR for OS was 0.77 (95% CI: 0.61- 0.96; P = 0.02). The pooled RRs for ORR, MRD negativity and CR were not statistically significant at 1.39 (95% CI: 0.69-2.82; P = 0.36), 1.02 (95% CI: 0.24-4.33; P = 0.98), and 2.29 (95% CI: 0.8-6.51; P = 0.12). Conclusions: Isatuximab based combination regimens significantly improved overall PFS and OS compared to control arm in patients with RRMM while benefits to ORR, MRD negativity and CR were not statistically significant. The improvement in PFS was noted in non-high-risk cytogenetic, non t(4,14), and non del (17p) cohorts and there was a trend towards PFS benefit in t(4,14) cohort. However, there were no PFS benefits in high-risk cytogenetic and del (17p) cohorts. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in these high-risk cytogenetic and del (17p) subsets.

End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA

Background : Lymphoma response criteria rely on PET/CT scans at end of therapy (EOT) to determine complete response (CR), which is necessary for cure. ~25% of patients achieve &amp;lt;CR by response criteria, but PET/CT scans have imperfect specificity and the positive predictive value of a single PET/CT scan at EOT is only ~50% (Kostakoglu 2021). To overcome this limitation, clinicians use additional tests including tissue biopsies or repeat PET/CT scans prior to salvage therapy to adjudicate positive results, but it remains unclear how often this occurs. Circulating tumor DNA (ctDNA) has improved tumor specificity that may reduce reliance on additional tests. We addressed these questions within a clinical trial delivering 1L therapy to pts with aggressive B-cell lymphoma. Methods : Pts were enrolled in a phase 2 study of DA-EPOCH-R or R-CHOP +/- acalabrutinib for treatment naïve DLBCL or high-grade B-cell lymphoma (HGBCL) [NCT04002947]. All pts were &amp;gt;18yrs old, stage II-IV, with adequate organ function. Pts completing induction therapy with available EOT PET/CT scans and EOT plasma samples were studied. PET/CT scans were interpreted by 2 nuclear medicine (NM) radiologists blinded to clinical outcomes using the 5-point Deauville Score (DS) with DS4/5 considered positive. Tissue biopsies and unplanned PET scans after the EOT PET/CT scan to determine remission status were recorded. Measurable residual disease (MRD) in plasma cfDNA was evaluated by Phased Variant Enrichment &amp; Detection Sequencing (PhasED-Seq) at Foresight Diagnostics blinded to clinical outcomes. Tumor derived Phased Variants (PVs) were identified from baseline pretreatment plasma samples or baseline tumor tissue, with matched constitutional DNA from paired PBMCs used to censor germline variants and CHIP. PVs were used to assess EOT MRD. Results were reported as MRD positive when ctDNA levels exceeded an analytical detection threshold (~1:10 6 cfDNA molecules) corresponding to 98% specificity. The prognostic utility of MRD was compared to standardized PET/CT scan at EOT to freedom-from-progression (FFP) and progression-free survival (PFS). Results : 55 enrolled pts completing planned therapy had EOT PET/CT and MRD analyzed. 54 (98%) pts were successfully genotyped and comprised the study population. Median age was 61 (range 26-85), including 22 (41%) female, 44 (81%) with advanced stage, and 26 (48%) with IPI score ³3. Pathologic subtypes included 24 (44%) GCB, 21 (39%) non-GCB, 8 (15%) HGBL-DH, and 1 (2%) THRLBCL. 43 (80%) pts received DA-EPOCH-R and 11 (20%) pts received R-CHOP. Twenty-six (48%) pts received acalabrutinib with R-chemotherapy. After 26 months median follow-up, the 2-year FFP and PFS of the cohort was 89% and 84%. Fourteen (26%) pts had a positive EOT PET/CT scan and 40 (74%) were negative. The concordance rate between the 2 NM radiologists on positive scans was 100%. Only 2 of 14 patients with a positive EOT PET/CT had clinical progression requiring salvage therapy (14% PPV). Nine (64%) of these pts required additional tests to determine remission status including 5 repeat PET/CT scans and 4 tissue biopsies. The 2-year PFS for pts with a positive vs negative EOT PET/CT was 66% vs 90% (p=0.08, Fig.A). Twelve (22%) pts had detectable EOT MRD and 42 (78%) were undetectable. 7 pts with detectable EOT MRD had clinical progression requiring salvage therapy or have died. While no pt with undetectable EOT MRD progressed, 1 (2%) died in remission of sudden cardiac death. Of 14 pts with positive EOT PET/CT, 7 (50%) had undetectable ctDNA and none progressed, suggesting MRD testing could have potentially rendered additional tests unnecessary. Conversely, patients with positive PET/CTs who progressed invariably had detectable ctDNA at EOT, suggesting utility of MRD for adjudicating PET/CT results. The 2-yr PFS for pts with detectable vs undetectable EOT MRD was 33% vs 98% (p&amp;lt;0.0001, Fig.B). At EOT, the PFS hazard ratio for MRD was 35.7, as compared with 3.1 for PET/CT. Conclusions : Response evaluations relying on PET/CT scans often require additional tests and procedures to assess remission status in aggressive B-cell lymphomas. Initiation of salvage therapy without adjudication in patients not achieving CR by EOT PET/CT scans will result in overtreatment. Given the higher specificity and PPV of EOT MRD, we propose an integrated response evaluation strategy combining these methods to reduce unnecessary additional tests and overtreatment.

FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes

Cancer cell resistance arises when tyrosine kinase inhibitor (TKI)-targeted therapies induce a drug-tolerant persister (DTP) state with growth via genetic aberrations, making DTP cells potential therapeutic targets. We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced anaplastic lymphoma kinase (ALK) fusion-positive DTP cell’s survival. FGFR1 signaling promoted DTP cell survival generated from basal FGFR1- and fibroblast growth factor 2 (FGF2)-high protein expressing cells, following alectinib treatment, which is blocked by FGFR inhibition. The hazard ratio for progression-free survival of ALK-TKIs increased in patients with ALK fusion-positive non-small cell lung cancer with FGFR1- and FGF2-high mRNA expression at baseline. The combination of FGFR and targeted TKIs enhanced cell growth inhibition and apoptosis induction in basal FGFR1- and FGF2-high protein expressing cells with ALK-rearranged and epidermal growth factor receptor (EGFR)-mutated NSCLC, human epidermal growth factor receptor 2 (HER2)-amplified breast cancer, or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma by preventing compensatory extracellular signal-regulated kinase (ERK) reactivation. These results suggest that a targeted TKI-induced DTP state results from an oncogenic switch from activated oncogenic driver signaling to the FGFR1 pathway in basal FGFR1- and FGF2-high expressing cancers and initial dual blockade of FGFR and driver oncogenes based on FGFR1 and FGF2 expression levels at baseline is a potent treatment strategy to prevent acquired drug resistance to targeted TKIs through DTP cells regardless of types of driver oncogenes.

Comparative effectiveness between mosunetuzumab monotherapy clinical trial and real-world data in relapsed/refractory follicular lymphoma in third or subsequent lines of systemic therapy

A comparison of clinical outcomes in the third or subsequent line (3 L+) of systemic therapy between a real-world data (RWD) external control cohort and a mosunetuzumab single-arm clinical trial cohort is presented. Data for 3 L + patients with relapsed/refractory follicular lymphoma (FL) were obtained from the mosunetuzumab single-arm trial (n = 90) and a US electronic health records database (n = 158), with patients meeting key eligibility criteria from the trial, balanced on pre-specified prognostic factors. Overall response and complete response rates were 80% and 60% in the mosunetuzumab cohort and 75% and 33% in the RWD cohort, odds ratios of 1.23 (95% CI, 0.52–2.93) and 3.18 (95% CI, 1.41–7.17), respectively. Hazard ratios for progression-free survival and overall survival were 0.82 (95% CI, 0.53–1.27) and 0.43 (95% CI, 0.19–0.94). These findings support a clinically meaningful benefit of mosunetuzumab monotherapy as a chemotherapy-free option for the 3 L + FL population.